Millions of people worldwide suffer from spinal cord injury (SCI) and most are at chronic stages. The rather daunting problems that the long-injured cord introduces to hinder the regrowth of damaged axon pathways has frustrated attempts to devise promising regenerative approaches especially for chronic cord injury. The glial scar that develops after trauma as well as the perineuronal net that forms a curtain around synapses throughout the CNS are major obstacles to axon regeneration, sprouting and functional recovery especially at chronic stages. The inhibition is due to the production of a family of potently inhibitory extracellular matrix molecules known as the chondroitin sulfate proteoglycans (CSPGs). The exciting discovery of the first known receptors on neurons that mediate the regrowth inhibitory effects of these molecules has opened the door to the production of specific blocking peptides that can be used to manipulate these receptors and when combined with an enzyme strategy can elicit recovery even at chronic stages. We have now devised a simple combinatorial method for overcoming CSPGs that employs microinjection of a long acting chondroitinase enzyme that breaks down the scar barrier locally plus a novel peptide called Intracellular Sigma Peptide or ISP that can be administered systemically and interferes with the neuronal proteoglycan receptor more globally. We hypothesize that our proposed studies can maximize the return of function at chronic time points after SCI using a minimally invasive strategy and explore fundamental mechanisms of synergistic enhancing effects by adding exercise therapy linked to the CSPG receptor modulation. In a comprehensive pilot experiment, the easily delivered, combined treatment fosters a good measure of recovery at chronic time points after contusive injury in a rodent model. Our goals now are to expand and maximize the recovery that occurs and with strong positive results, there is continued hope that there will be translational success in humans.